Biology subjects

Maloney, B.

Publications and source records attributed to Maloney, B..

3 recordsLinked to original sources

bioRxiv2026

Oral administration of 1,10-phenanthroline-5-amine (PAA) significantly reduced amyloid plaque burden compared with untreated APP/PS1 mice.

BackgroundWe previously demonstrated that 1,10-phenanthroline-5-amine (PAA) significantly reduced the number and size of amyloid plaques in one-year-old APP/TAU mice. The primary objective of the present study was to validate these findings in the APP/PS1 mouse model using a larger cohort of animals. A second objective was to determine whether PAA binds directly to amyloid plaques in brain tissue sections. MethodsFor the in vivo studies, APP/PS1 mice received daily oral PAA or vehicle treatment and were euthanized at one year of age. Brains were collected, fixed, cryosectioned, and stained with hydroxyquinoline oxalate (HQ-O) to visualize amyloid plaques. For the in vitro studies, brain tissue sections were incubated in a PAA solution. Double labeling with PAA and HQ-O was performed on the same tissue sections to compare plaque labeling patterns. ResultsDaily oral administration of PAA produced a significant reduction in both the number and size of amyloid plaques compared with untreated control mice. In vitro incubation of tissue sections with PAA resulted in red fluorescent labeling of all amyloid plaques. Double-labeling studies showed that PAA labeled plaques are more extensive than HQ-O in frozen tissue sections, whereas no such difference was observed in paraffin-embedded sections. ConclusionsThese findings extend our previous observation that chronic oral administration of PAA significantly reduces amyloid plaque burden in vivo. In addition, the in vitro studies demonstrate that PAA binds directly to amyloid plaques. The mechanism of PAA binding may involve interactions with transition metals incorporated within amyloid plaques and/or the sialic acid moieties of plaque-associated gangliosides.

neuroscience↗

bioRxiv2024

Persistent genomic erosion in whooping cranes despite demographic recovery

Integrating in-situ (wild) and ex-situ (captive) conservation efforts can mitigate genetic diversity loss and help prevent extinction of endangered wild populations. The whooping crane (Grus americana) experienced severe population declines in the 18th century, culminating into a collapse to 16 individuals in 1941. Legal protections and conservation actions have since increased the population to approximately 840 individuals, yet the impact on genomic diversity remains unclear. We analysed the temporal dynamics of genomic erosion by sequencing a high-quality genome reference, and re-sequencing 16 historical and 37 modern genomes, including wild individuals and four generations of captive-bred individuals. Genomic demographic reconstructions reveal a steady decline, accelerating over the past 300 years with the European settlement of North America. Temporal genomic analyses show that despite demographic recovery, the species has lost 70% of its genetic diversity and has increased their inbreeding. Although the modern population bottleneck reduced the ancestral genetic load, modern populations possess more realized load than masked load, possibly resulting in a chronic loss of fitness. Integrating pedigree and genomic data, we underscore the role of breeding management in reducing recent inbreeding. Yet ongoing heterozygosity loss, load accumulation, and background inbreeding argues against the species downlisting from their current Endangered status on the IUCN Red List and the Endangered Species Act. The presence of private genetic variation in wild and captive populations suggests that wild-captive crosses could enhance genetic diversity and reduce the realized load. Our findings emphasize the role of genomics in informing conservation management and policy.

evolutionary biology↗

bioRxiv2024

Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.

Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid-{beta} precursor protein (APP) and -synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cell lines and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with a reduced probability of AD, while elevated REST may associate with a greater probability of AD. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reduced expression of APP, SNCA and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.

neuroscience↗